Lenalidomide, Cytarabine, and Idarubicin in Treating Patients With Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of lenalidomide in combination with
conventional chemotherapy in two separate cohorts of patients with 1) relapsed or refractory
acute myeloid leukemia (AML) and 2) age >= 60 with untreated AML and recommend starting
doses for phase II studies of this combination of agents.

SECONDARY OBJECTIVES:

I. To define the qualitative and quantitative toxicities of these combinations of agents in
regard to organ specificity, time course, predictability, and reversibility.

II. To document the therapeutic response of these combinations of agents in patients with
poor risk AML.

III. To conduct pharmacodynamic studies to investigate the potential mechanism of
lenalidomide activity in this trial.

OUTLINE: This is a dose-escalation study of lenalidomide.

INDUCTION:

COHORT I: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21, cytarabine
intravenously (IV) continuously over 96 hours on days 5-8, and idarubicin IV over 1 hour on
days 5-7.

COHORT II: Patients receive lenalidomide PO QD on days 1-21, cytarabine IV continuously over
24 hours on days 5-11, and idarubicin as above.

Patients with residual disease on day 18 undergo a second course of induction therapy.

CONSOLIDATION:

COHORT I: Patients receive lenalidomide PO QD on days 1-14, idarubicin IV over 1 hour on
days 5-6, cytarabine IV continuously on days 5-7. Treatment continues for 1 course in the
absence of disease progression or unacceptable toxicity.

COHORT II: Patients 2 receive 4 courses of consolidation therapy comprising lenalidomide PO
QD on days 1-14 and cytarabine IV every 12 hours on days 5, 7, and 9. Treatment repeats
every 28 days for up to 4 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Cohort 1: Patients must be age >= 18 and < 65 with relapsed or refractory AML or high
risk myelodysplastic syndrome (MDS); high risk MDS is defined as international
prognosis scoring system (IPSS) score of 1.5 or higher; eligible patients will have a
score of 1.5 or higher at any time from diagnosis to screening

- Cohort 2: Patients must be age >= 18 with previously untreated AML; favorable
risk AML patients < 60 years of age are excluded; these are defined as core
binding factor (CBF) AML patients and characterized by cytogenetic or molecular
evidence of CBF leukemia; untreated AML patients < 60 years of age must be
negative on screening for CBF leukemia by cytogenetic or molecular analysis
(Note: Prior therapy for MDS is permitted)

- Patients with secondary AML or therapy-related disease (transformed [t]-AML/MDS) are
eligible

- If the patient has co-morbid medical illness, life expectancy attributed to this must
be greater than 6 months

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Total bilirubin < 2.0 mg/dL

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 2.5 times upper
limit of normal

- Creatinine < 2.0 mg/dL AND creatinine clearance (calculated) >= 50 mL/min

- Left ventricular ejection fraction (LVEF) >= 40%

- Patients who have previously received lenalidomide, idarubicin, and/or cytarabine are
eligible provided that the combination of the 3 agents has never before been
administered, and that no lenalidomide has been administered for at least 6 months

- Females of childbearing potential (FCBP) must have a negative serum or urine
pregnancy test with a minimum sensitivity of at least 25 mIU/mL within 10-14 days
prior to and again within 24 hours of starting lenalidomide and must either commit to
continued abstinence from heterosexual intercourse or begin TWO acceptable methods of
birth control, one highly effective method and one additional effective method AT THE
SAME TIME, at least 28 days before she starts taking lenalidomide; FCBP must also
agree to ongoing pregnancy testing; men must agree to use a latex condom during
sexual contact with a FCBP even if they have had a successful vasectomy; these
methods of birth control must be used for the duration of study participation and for
28 days after lenalidomide discontinuation; all patients must be counseled at a
minimum of every 28 days about pregnancy precautions and risks of fetal exposure

- Ability to understand and willingness to sign the written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study, or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients who have taken lenalidomide within the last 6 months

- Patients receiving any other investigational agents or patients that have received
other investigational agents within 14 days of enrollment

- Patients with active central nervous system disease or with granulocytic sarcoma as
sole site of disease

- Patients with history of medically serious allergic reactions or non-hematologic
toxicities attributed to the agents in this trial such as lenalidomide or thalidomide
or compounds of similar chemical or biologic composition that are not easily managed,
or patients with a history of cerebellar toxicity to cytarabine

- Patients with the following will be excluded: uncontrolled intercurrent illness
including, but not limited to, symptomatic congestive heart failure, unstable angina
pectoris, serious cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements, myocardial infarction within 6 months
prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure,
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of
acute ischemia or active conduction system abnormalities; patients with medical
comorbidities that will preclude safety evaluation of the combination should not be
enrolled

- Patients with serious medical or psychiatric illness likely to interfere with
participation in this clinical study

- Pregnant women or women who are breastfeeding; additional pregnancy testing before,
during, and after lenalidomide treatment is required, as well as requirements for
contraception before, during, and after lenalidomide treatment

- Patients with advanced malignant solid tumors are excluded; patients with active
additional hematologic malignancies are excluded

- Patients with a history of neurologic toxicity with cytarabine are excluded

- As infection is a common feature of AML, patients with active infection are permitted
to enroll provided that the infection is under control; patients with uncontrolled
infection shall not be enrolled until infection is treated and brought under control

- Known human immunodeficiency virus (HIV)-positive patients are ineligible;
appropriate studies will be undertaken in HIV + patients once safety of the
combination has been demonstrated